Τίτλος:
Targeting on poly(ADP-ribose) polymerase activity with DNA-damaging hybrid lactam-steroid alkylators in wild-type and BRCA1-mutated ovarian cancer cells
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Conjugated lactam-steroid alkylators (LSA) have been shown to exhibit superior activity at controlling cancer models and overlap drug resistance to conventional chemjournalapy. Hybrid LSA combine two active compounds in a single molecule and incorporate modified steroids bearing lactam moiety in one or more steroid rings functioning as vectors for cytotoxic agents. We first describe a novel class of LSA that generate excellent anticancer activity against UWB1.289 and UWB1.289 + BRCA1 human ovarian cancer cell lines. Both UWB1.289 and UWB1.289 + BRCA1 cells carry mutations in the tumor suppressor gene TP53 while UWB1.289 cell line carries a germline BRCA1 mutation. In vitro, in vivo, and in silico, experimental methods were utilized to determine the poly(ADP-ribose) polymerases (PARPs) activity and mRNA transcription, DNA damage, cytostatic and cytotoxic effects, and virtual molecular interactions, in order to study the molecular mechanisms of activity of the tested LSA. LSA produce anticancer activity through dual action by combining the direct induction of cellular DNA damage with the inhibition of PARP activity and consecutive DNA repair activity. BRCA1-mutated UWB1.289 ovarian cancer cells with defective PARP-oriented repair mechanism show significantly higher sensitivity to these agents. Combined drug effect on DNA damage and repair is a novel approach in cancer therapeutics. © 2017 John Wiley & Sons A/S.
Συγγραφείς:
Trafalis, D.T.
Polonifi, A.
Dalezis, P.
Nikoleousakos, N.
Katsamakas, S.
Sarli, V.
Περιοδικό:
Chemical Biology and Drug Design (formerly Journal of Peptide Research)
Εκδότης:
Wiley-Blackwell Publishing Ltd
Λέξεις-κλειδιά:
alkylating agent; BRCA1 protein; cell DNA; lactam steroid alkylator; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 2; unclassified drug; alkylating agent; antineoplastic agent; BRCA1 protein; BRCA1 protein, human; lactam; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; steroid, antineoplastic activity; antiproliferative activity; Article; cancer growth; controlled study; crystal structure; DNA damage; DNA repair; enzyme activity; female; gene expression; gene mutation; gene targeting; genetic transcription; genotoxicity; human; human cell; hydrogen bond; IC50; in vitro study; in vivo study; molecular docking; molecular interaction; mouse; nonhuman; polymerase chain reaction; priority journal; tumor suppressor gene; UWB1.289 cell line; chemistry; DNA damage; drug effects; genetics; metabolism; mutation; Ovarian Neoplasms; tumor cell line, Alkylating Agents; Antineoplastic Agents; BRCA1 Protein; Cell Line, Tumor; DNA Damage; Female; Humans; Lactams; Molecular Docking Simulation; Mutation; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Steroids
